Haploinsufficiency of<i>Syngap1</i>in Striatal Indirect Pathway Neurons Alters Motor and Goal-Directed Behaviors in Mice

<i>SYNGAP1</i> is a high-confidence autism spectrum disorder (ASD) risk gene, and mutations in <i>SYNGAP1</i> lead to a neurodevelopmental disorder (NDD) that presents with epilepsy, ASD, motor developmental delay, and intellectual disability. <i>SYNGAP1</i> codes for Ras/Rap GTP-ase activating protein SynGAP (SynGAP). SynGAP is located in the postsynaptic density of glutamatergic synapses and regulates glutamate receptor trafficking in an activity-dependent manner. In addition to forebrain glutamatergic neurons, <i>Syngap1</i> is highly expressed in the striatum, although the functions of SynGAP in the striatum have not been extensively studied. Here we show that <i>Syngap1</i> is expressed in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs) in mice of both sexes. In a mouse model of <i>Syngap1</i> haploinsufficiency, dendritic spine density, morphology, and intrinsic excitability are altered primarily in iSPNs, but not dSPNs. At the behavioral level, SynGAP reduction alters striatal-dependent motor learning and goal-directed behavior. Several behavioral phenotypes are reproduced by iSPN-specific <i>Syngap1</i> reduction and, in turn, prevented by iSPN-specific <i>Syngap1</i> rescue. These results establish the importance of SynGAP to striatal neuron function and pinpoint the indirect pathway as a key circuit in the neurobiology of <i>SYNGAP1</i>-related NDD.